Candida species are opportunistic fungal pathogens that have become among the most common causes of nosocomial infections in the United States and worldwide. Disseminated infections caused by Candida spp. have increased 15-fold in incidence in the last 15 years, and Candida is now the third most common cause of bloodstream infections. Even with modern antifungal therapy, disseminated candidiasis has an unacceptable attributable mortality of 40%- 50%. Furthermore, resistance to conventional antifungal therapies among Candida spp. is rising. For these reasons, a vaccine to prevent life threatening Candida infections in patients who are acutely at risk is particularly attractive. Estimates indicate that millions of high risk patients per year in the United States (U.S.) alone could benefit from such a vaccine. We have isolated Candidal protein adhesins that stimulate potent anti-Candida immune responses in mice. Through work completed as a result of our Phase I STTR grant, we confirmed that the recombinant N-terminus of Als3p (rAls3p-N) was the optimally effective immunogen, resulting in significant protection against hematogenously disseminated, vaginal, and oropharyngeal candidiasis. We have also determined that alum, the only vaccine adjuvant approved for use in humans by the US Food and Drug Administration (FDA), is an effective adjuvant in combination with rAls3p-N. To complete pre-clinical testing, the following aims will be accomplished in the current Phase II STTR application: 1) Establish Good Manufacturing Practice for the rAls3p-N vaccine;2) Complete pre-clinical toxicity studies in support of an IND application;3) Develop high throughput assays to measure immunogenicity as surrogate markers for efficacy to be used in future clinical trials;and 4) To develop a phase I clinical protocol and related documents to support an Investigational New Drug application. At the end of the funding period, an IND application will be submitted in support of a phase I clinical trial to determine the safety and immunogenicity of the rAls3p-N vaccine. In support of the IND application, a clinical protocol and investigator's brochure will be developed, and documents in support of a pre-IND meeting and the IND will be prepared. The IND will be submitted in the final year of funding. Completion of the proposed Phase II STTR plan will finalize pre-clinical testing of the rAls3p-N, anti-Candidal vaccine, and will allow subsequent initiation of a phase I clinical trial to test the safety and immunogenicity of the vaccine in humans. Finally, we will develop humoral and cell-mediated immunological surrogate efficacy markers to lay the groundwork for immunological testing in humans in a phase Ib clinical trial. PUBLIC HEALTH RELEVANCE: Due to modern therapeutic advances for sustained life support, patients undergoing a variety of medical procedures or with a variety of medical conditions have become at risk for developing life-threatening infections caused by the fungus Candida. Among these procedures and conditions are: being treated in an intensive care unit, having a plastic catheter in a large vein, undergoing surgery to the chest or abdomen, being the victim of trauma injuries (both domestic, such as motor vehicle accidents, and military), having extensive burn injuries, being a premature neonate, and having cancer and undergoing chemotherapy. Given how common these conditions are, the development of a vaccine that protects against Candida infections could save hundreds of thousands of lives as well as substantially reduce hospitalization costs in both the United States and other countries where highly effective medical advances have been made.